Major Histocompatibility Complex (MHC) is
cluster of genes encoding polymorphic cell–surface molecules (MHC class I and
class II) that are involved in interaction with T cells. These molecules also
play a major role in transplantation rejection. Several other nonpolymorphic
proteins are encoded in this region. The MHC is referred to as “complex”
because the genes are closely linked and inherited as a unit. The set of genes
inherited by an individual from one parent is known as a haplotype.
MHC molecules have two critical functions:
(1) to bind to peptides derived from protein antigens, and (2) once peptide has
bound, to interact with a TCR. T–cell receptor (TCR) is a two–chain structure
on T cells that binds antigen: αβ on the major set of T cells, ϒδ on the minor set of T
cells. The TCR complex comprises the antigen–binding chains associated at the
cell surface with the signal transduction molecules CD3 plus ζ (zeta) or η
(neta).
The Human Leukocyte Antigen contains the
genes coding for the polymorphic MHC class I and II class molecules and many other
important genes and is located on chromosome 6.
Two
major sets of MHC genes and products:
1. MHC
class I is a molecule encoded by genes of the MHC
that participates in antigen presentation to CD8+ (cytotoxic) T cells. MHC
class I molecules are always expressed at the surface in association with a
molecule known as β2–microglobulin (β2m).
The
three independent human MHC class I genes and their cell surface products:
a. HLA–A
b. HLA–B
c. HLA–C
2. MHC
class II is a molecule encoded by genes of the MHC
that participates in antigen presentation to CD4+ T cells.
The
three independent human MHC class II genes and their cell surface products
which all consist of α and β chain:
a. HLA–DP
– the DPα chain always pair with DPβ and not with DQβ or DRβ, and the other
pair of chains behave similarly. The α and β chain of each molecule are coded
by an A and a B gene, respectively. The genes coding for DP α and β are known
as DPA1 and DPB1, and for DQ α and β, DQA1 and DQB1, respectively.
b. HLA–DQ
c. HLA–DR
– comprises approximately of seven known DRB genes and one A gene: the product
of the A gene DRA1 combines with the product of one of the DRB genes to
generate a DR αβ molecule.
Variables
in MHC genes and products:
1. Genetic
polymorphism
The
phenomenon of having multiple stable forms of one gene in the population is
known as genetic polymorphism. The MHC is the most highly polymorphic gene
system in the body, and hence in the population. This extensive polymorphism of
MHC genes therefore makes it very unlikely that two random individuals will
express identical sets of MHC molecules. Polymorphism is the basis for rapid
graft rejection between genetically different individuals.
2. Pattern
of expression
MHC
class I molecules are expressed on almost every nucleated cell in the body. MHC
class II molecules have a somewhat more limited distribution than class I
molecules: they are expressed under all conditions only on B lymphocytes,
dendritic cells, and thymic epithelial cells. Nonetheless, many other cells, such
as macrophages and endothelial cells, may be induced to express MHC class II
molecules by activating factors such as IFN–ϒ.
The
expression of MHC class I molecule is coordinate, in that all three MHC class I
molecules are expressed on the cell surface at the same time. Similarly, MHC
class II molecules are also coordinately expressed, but under distinct
regulation. Thus, MHC class I molecules can be expressed in the absence of any
MHC class II molecule. The level of MHC class I and II expression at the cell
surface can be coordinately upregulated or downregulated by a number of
stimuli.
In
the absence of inducing factors, most cells express MHC class I molecules
without expressing MHC class II molecules. Certain cells, such as B cells,
constitutively express both MHC class I and class II molecules. By contrast,
very few, if any, cells express MHC class II in the absence of MHC class I.
3. Codominant
Expression
Codominant
expression means that each of the cell of MHC class I and II are transcribed
from both maternal and paternal chromosomes. As a consequence of codominant
expression of MHC molecules, each cell within an individual therefore expresses
six different MHC class I molecules and between 10 to 20 different MHC class II
molecules.
Function
of MHC molecules
1. Antigen
processing and presentation
To
activate the T–cell response to any foreign protein, the protein must be broken
down into peptides, at least one of which must bind to and MHC molecule.
Protein catabolism to peptides takes place in two cellular compartments: (1)
within acid vesicles and (2) within the cytoplasm. Peptides generated in acid
vesicles bind to newly synthesized MHC class II molecules, whereas peptides
generated in the cytoplasm bind to newly synthesized MHC class I molecules. The
interaction of peptide with MHC molecules and the movement of peptide–MHC
complexes through the cell to the cell surface are facilitated by a series of
molecular chaperones.
a. Generation
of MHC Class II – Peptide Complexes
Exogenous antigens
(e.g., dead virus vaccine) are taken into cells by endocytosis if the antigen
is soluble or by phagocytosis, in specialized cells such as macrophages, if the
antigen is particulate. These exogenous antigens include bacteria, viruses
taken up by macrophages, and potentially harmless foreign proteins, such as
ovalbumin or sheep red blood cells.
Once
internalized, the antigen is contained in an intracellular vesicle that then
fuses with existing endosomal or lysosomal vesicles. The endosomal and
lysosomal vesicles are highly acidic (pH ~ 4.0) and contain an array of
degradative enzymes like proteases, peptidases and cathepsins.
Acid
vesicles containing the immunogenic peptides derived from protein antigens
intersect with vesicles containing newly synthesized MHC class II molecules.
MHC class II α and β chains are synthesized on ribosomes of the rough endoplasmic
reticulum (ER). The chains associated in the ER with a molecule known as
invariant chain (Ii, CD74); a region of the Ii interacts with the groove of the
newly formed MHC class II molecule, preventing the binding of endogenous
peptides found in the ER. Ii also acts as “chaperone” for the newly synthesized
MHC class II chains: interaction with Ii allows the MHC class II α plus β
chains to leave the ER and enter the endocytic pathway. Removal of Ii from the
complex occurs in stages in acid vesicles; initially, Ii is degraded
proteolytically, leaving a fragment known as CLIP (class II–associated
invariant chain peptide) bound to the MHC class II groove.
In
acid vesicles containing peptides derived from exogenous antigens, a molecule
known as HLA–DM facilitates peptide exchange between the MHC class II – CLIP
complex and peptides derived from exogenous antigens. In this way, a peptide –
MHC class II complex is generated, which then moves to the cell surface where
it can interact with a CD4+ T cell expressing the appropriate receptor.
The
association of MHC class II molecules and processed peptides is selective for
peptides between approximately 12 and 20 amino acids in length, and a single
peptide binds with high affinity to some but not other allelic forms of
molecule. The sequence and charge of the amino acids forming the peptide–binding groove of the MHC molecule determine which processed peptides are
accommodated.
b. Generation
of MHC Class I – Peptide Complexes
Endogenous antigens
(e.g. viral or parasitic protein) are synthesized within the cell at the
cytosolic compartment instead of acid vesicles.
The
major mechanism for generating peptide fragments in the cytoplasm is via a
giant protein complex known as the proteasome. The proteasome cuts the protein
into peptide fragments 8 to 9 residues long and these peptides are selectively
transported into the ER by the products of two transporter genes, known as TAP–1
and TAP–2.
Binding
of peptides with newly synthesized MHC class I molecules takes place in the ER.
Binding of peptide to MHC class I molecules is also selective, based on the
structure of the binding groove of the MHC class I molecule and the peptide.
Because the groove in the MHC class I binding site is closed at both ends, MHC
class I molecules preferentially bind peptides of 8 – 9 amino acids in length,
the length which results from cutting by the cytosolic proteasome.
Before
peptide loading, the MHC class I and β2–microglobulin chains synthesize in the
ER associate with chaperones, which assist in the correct folding of the MHC
class I plus β2–microglobulin and directing the molecule through the ER.
Peptide that binds to an MHC class I molecule in the ER moves via the Golgi apparatus
to the cell surface where it may interact with a CD8+ T cell
expressing the appropriate receptor.
2. MHC
molecules bind peptides derived from self–molecules
As
a consequence of the normal pathways of intracellular turnover and metabolism
of cellular constituents, peptides derived from self–components such as
ribosomal and mitochondrial proteins can also bind to MHC molecules. These self–components
do not, however, generally result in T–cell activation. Either these components
are present at a number too low to activate T cells or the T cells have been
made tolerant to this combination of MHC and peptide.
Only
a small number of MHC–foreign peptide complexes is required at the surface of
the APC to generate immune response. It is believed that as few as 80 – 100 MHC–foreign
peptide complexes on the surface of a cell are sufficient to trigger a T–cell
response.
3. Inability
to respond to antigen
For
an antigen to generate a T–cell response, at least one peptide derived during
processing must bind to one of these MHC molecules. A peptide that does not
bind to an MHC molecule does not activate a T–cell response. Thus, it is
possible that some individuals may respond to a small peptide, but other MHC–distinct
individuals may not. If an entire antigen fails to generate a single peptide
able to bind to an MHC molecule, the individual will not mount a T–cell
response to that particular antigen. An inability to respond to naturally
occurring pathogens is very rare, as pathogens generally contain multiple
epitopes.
4. One
antigen can trigger MHC Class I– or Class II–restricted responses
For
example, if a viral antigen it taken up by macrophages such as vaccine with a
non–infectious viral particle, processing occurs in acid vesicles and
peptides bind to MHC class II molecules.
If,
however, the same viral antigen is synthesized following the infection of a
cell, processing occurs in the cytoplasm of the cell and peptides associate
with MHC class I molecules. The peptides that associate with MHC class I may be
different from those that bind to MHC class II. Thus, as a consequence of the
selective binding of peptides to MHC molecules, CD4+ and CD8+
T cells in one individual may respond to different epitopes on the same
antigen.
Comparison
of the properties and function of MHC Class I and Class II
MHC Class I
|
MHC Class II
|
|
Structure
|
α chain + β2m
|
α and β
|
Domains
|
α1, α2, α3
+ β2m
|
α1 + α2 and β1
+ β2
|
Constitutive cellular
expression
|
Nearly all nucleated cells
|
Antigen presenting cells (B cells,
dendritic cells, thymic epithelial cells)
|
Peptide binding
groove
|
Closed, binds 8 – 9 amino acid peptides
formed by α1 and α2 domains
|
Open, binds 12 – 20 amino acid peptides
formed by α1 and β1 domains
|
Peptide derived
from
|
Endogenous antigens, catabolized in the
cytoplasm
|
Exogenous antigens, catabolized in acid
compartments
|
Peptide presented to
|
CD8+ T cells
|
CD4+ T cells
|
β2m – beta 2 macroglobulin
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